European Respiratory Society
Respiratory Diseases of the Newborn Infant

So much of our lung health throughout life is determined by what happens before birth and when we are born. Managing respiratory problems in newborn infants requires experience and teamwork, an understanding of the background to the problems, and knowledge of the evidence behind the clinical options available. In this Monograph, science, evidence and expertise are brought together in a collection of comprehensive, state-of-the-art reviews that cover: the structure and function of the newborn respiratory system; neonatal lung disease in preterm infants; developmental, structural and functional diseases of the respiratory system; and more. This book will prove a valuable resource for neonatal clinicians, scientists researching the area and adult clinicians managing lung health.

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    1. Page 1
      Abstract
      Daniel T. Swarr, Cincinnati Children's Hospital Medical Center, Division of Neonatology, Perinatal and Pulmonary Biology, Dept of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA. E-mail: Daniel.Swarr@cchmc.org

      Throughout the course of human development, the lung progresses from a simple bud derived from the embryonic foregut into a complex, highly branched structure capable of providing sufficient surface area for gas exchange in order to meet the body's metabolic demands. The lung must be able to pass large amounts of blood across delicate alveolar structures without bleeding, remove fluid from the interstitial space, prevent excessive fluid losses, defend against infectious organisms and toxins, and sense and respond appropriately to physiological stimuli. This chapter will review the developmental and molecular mechanisms that lead to the formation of this complex structure and the dozens of cell types that form the human lung, with a focus on recent advances in cell lineage-fate analysis, single-cell sequencing and three-dimensional culture model systems. We also outline how disruption of any of these key developmental processes can lead to various congenital, paediatric or adult lung diseases.

      Cite as: Swarr DT, Deshmukh H, Zacharias W. In utero and post-natal development of the human lung and its defence mechanisms. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 1–20 [https://doi.org/10.1183/2312508X.10013320].

    2. Page 21
      Abstract
      Antonella LoMauro, Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Piazza Leonardo Da Vinci, 20133 Milan, Italy. E-mail: antonella.lomauro@polimi.it

      Respiratory system development starts in utero and continues in the post-natal period, at least up to 2–3 years of age. The intra-uterine development prepares the neonate for the transition from fetal to post-natal life. Development after birth enables the respiratory system to meet the increased metabolic demands during infancy and childhood. Therefore, the newborn respiratory system is not a small version of the adult one. Respiratory system resistance is high and compliance is low, due to the small airways and lung size. The floppy chest wall is associated with low resting volume and paradoxical breathing. The thorax has a cylindrical shape that puts the respiratory muscles at a mechanical disadvantage, and the diaphragm seems more susceptible to fatigue. The breathing pattern is very irregular due to immature control and is characterised by high breathing rates. This chapter covers the most important features of healthy newborn respiratory physiology.

      Cite as: LoMauro A, Zannin E. Respiratory physiology. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 21–37 [https://doi.org/10.1183/2312508X.10013420].

    1. Page 38
      Abstract
      Steven M. Donn, 8621 C.S. Mott Children's Hospital, 1540 E. Medical Center Drive, Ann Arbor, MI 48109-4254 USA. E-mail: smdonnmd@med.umich.edu

      Birth is usually a physiologically normal event, and the majority of fetuses successfully transition to life outside the womb. Occasionally, however, for a variety of reasons, this transition may fail to occur, and affected infants require respiratory support in the delivery suite and the NICU. In this chapter, we highlight the principles of neonatal resuscitation and respiratory support. We review the types of equipment used in the delivery suite, the principles of mechanical ventilation, and offer a ten-step strategy for individualised patient support based on pathophysiology.

      Cite as: Stepanovich G, Donn SM. Respiratory support in the delivery suite and the NICU. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 38–49 [https://doi.org/10.1183/2312508X.10013520].

    2. Page 50
      Abstract
      Ivana Mižíková, Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, 501 Smyth Box 511, ON K1H 8L6, Ottawa, ON, Canada. E-mail: mizikova.ivana@gmail.com

      BPD is a heterogeneous disease of multi-factorial origin. Morbidity and severity of BPD are directly associated with degree of prematurity, pre-natal and post-natal inflammation, invasive mechanical ventilation and exposure to increased oxygen levels. Ventilation and hyperoxia activate immune cells, particularly neutrophils and alveolar macrophages, which initiate a powerful inflammatory response. Released pro-inflammatory mediators further activate pro-fibrotic factors, such as transforming growth factor-β, proteases and matrix-remodelling enzymes, leading to perturbations in extracellular matrix deposition, microvascular formation and secondary septation, as well as restricted regenerative capacity of the lung. Additionally, under-differentiated cell populations fail to develop and carry out their functions properly. The extent and permanence of the damage are directly proportional to the severity and duration of injurious stimuli. Most recent promising therapeutic interventions include minimally invasive surfactant therapy, avoidance of mechanical ventilation, and modified regimens for post-natal steroids. Most promising current laboratory investigations focus on anti-inflammatory mediators and cell-based therapies.

      Cite as: Mižíková I, Alejandre Alcazar MA, Thébaud B. Pathogenesis of BPD. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 50–67 [https://doi.org/10.1183/2312508X.10013620].

    3. Page 68
      Abstract
      Anne Greenough, Neonatal Intensive Care Unit, 4th Floor Golden Jubilee Wing, King's College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK. E-mail: anne.greenough@kcl.ac.uk

      BPD is now the most common adverse outcome of very premature birth; this is largely due to the increased survival of affected infants and the routine use of antenatal corticosteroids and postnatal surfactant. Unfortunately, individuals who have had BPD can suffer chronic respiratory morbidity including: prolonged supplementary oxygen dependency; rehospitalisations due to respiratory problems in the first 2 years after birth; and troublesome respiratory symptoms and lung function abnormalities even into adulthood. “BPD” children and adults also have a higher incidence of severe neurological problems such as cerebral palsy and delayed neurodevelopment compared to either healthy term born adults or prematurely born infants without BPD. Studies have demonstrated that their lung function may deteriorate prematurely, that is before puberty, putting them at risk of the early development of COPD. Affected individuals require long-term pulmonary follow-up and the complex and diverse clinical needs of these children and adults mandate coordinated interdisciplinary care.

      Cite as: Dassios T, Greenough A. Long-term sequelae of BPD. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 68–78 [https://doi.org/10.1183/2312508X.10013720].

    4. Page 79
      Abstract
      Katie Rose, Respiratory Unit, Alder Hey Children's NHS Foundation Trust, Eaton Road, Liverpool L12 2AP, UK. E-mail: Katierose100@gmail.com

      Infants with BPD are at risk of many short- and long-term complications, which can have lifelong consequences. There is a window of opportunity in the first years of life to optimise lung growth and function while limiting further insults to the respiratory and other organ systems. A multidisciplinary approach is required to address the needs of these vulnerable infants in the BPD clinic while minimising the significant burden on parents and carers. Educating families empowers them to understand the aims of management and actively participate in the care of their children with an emphasis on shared decision making, which often starts in the NICU for these families. In this chapter, we will discuss considerations in the design of BPD clinics, addressing optimal nutrition for these children, managing home oxygen therapy, and the prevention of further lung damage with protection against infection and promotion of a healthy lifestyle, all ultimately promoting lifelong respiratory health.

      Cite as: Rose K, Woodland C, Murphy G, et al. Management of BPD: strategies to prevent short- and long-term complications following discharge from the NICU. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 79–88 [https://doi.org/10.1183/2312508X.10013820].

    5. Page 89
      Abstract
      Caroline B. Jones, Paediatric Cardiology, Alder Hey Children's NHS Foundation Trust, Eaton Road, Liverpool, L12 2AP, UK. E-mail: Caroline.b.jones@alderhey.nhs.uk

      The diagnosis and management of PH in the preterm neonate remains both challenging and controversial. Lack of clinical consensus around diagnostic definitions, classification and echocardiographic assessment persists. PH is often multifactorial following preterm birth with complex cardiorespiratory interactions, a transitional circulation with frequently persisting cardiovascular shunts. Lung developmental disorders are one of the primary contributors to PH in the preterm infant, most commonly BPD. These infants remain some of the most challenging patients to treat in neonatal and respiratory medicine, with PH and its sequelae responsible for considerable morbidity and mortality. In recent decades, new PH therapies have shown substantial benefit in term neonates; however, evidence remains lacking for their use in preterm infants. Echocardiographic assessment is a key bedside tool for defining this disease and targeting therapeutic strategies. Consensus on definitions, diagnosis and disease classification is required to standardise study design and refine treatment pathways in these challenging patients.

      Cite as: Jones CB, Johns M. Pulmonary hypertension in preterm infants. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 89–103 [https://doi.org/10.1183/2312508X.10013920].

    6. Page 104
      Abstract
      Ramana Dhannapuneni, Dept of Cardiac Surgery, Alder Hey Children's Hospital NHS Trust, Eaton Road, Liverpool L12 2AP, UK. E-mail: ram.dhannapuneni@alderhey.nhs.uk

      The optimal management of the patent ductus arteriosus (PDA) in the premature infant remains controversial. Whilst considerable historical studies indicate that prolonged exposure to a significant PDA is deleterious, robust evidence of long-term benefit from treatment is currently lacking. Physiologically, delayed PDA can result in pulmonary overcirculation and systemic hypoperfusion and is associated with increased mortality and neonatal morbidities including BPD, necrotising enterocolitis, intraventricular haemorrhage and a late sequela of PH. In a subset of premature infants with haemodynamically significant PDA, particularly those requiring inotropic support and prolonged ventilatory support, earlier ductal closure before the onset of elevated pulmonary artery pressure has been associated with faster respiratory and inotropic weaning and improved weight gain. Current management options are conservative, pharmacotherapy, surgical ligation, or transcatheter closure, each with advantages and drawbacks. Ultimately, the calculation is a clinical one based on the short- and long-term effect of PDA treatment, rather than the method of treatment.

      Cite as: Dhannapuneni RRV, Kang S-L, Subhedar NV. When and how to close patent ductus arteriosus in a preterm infant. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 104–117 [https://doi.org/10.1183/2312508X.10014020].

    7. Page 118
      Abstract
      Woolf T. Walker, Primary Ciliary Dyskinesia Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. E-mail: Woolf.walker@uhs.nhs.uk

      PCD is a rare, generally autosomal recessive inherited condition. Abnormal ciliary function leads to impaired mucociliary clearance that, characteristically, results in recurrent sinopulmonary infections and leads to bronchiectasis. The clinical presentation in children, with wet cough and rhinitis, is often not recognised as different from other children of their age and hence leads to a delay in diagnosis. However, most newborns with PCD have significant NRD. This presents an important opportunity for early recognition of the condition by neonatologists, leading to referral for diagnostic testing and prompt initiation of treatment, which should improve patient outcomes. In this chapter we will therefore highlight the clinical features of PCD in the neonatal period, the diagnostic tests for the condition and its management.

      Cite as: Walker WT, Everitt LH. Primary ciliary dyskinesia. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 118–132 [https://doi.org/10.1183/2312508X.10020020].

    8. Page 133
      Abstract
      Jayesh Mahendra Bhatt, Dept of Respiratory Paediatrics, Nottingham Children's Hospital, Queen's Medical Centre, Derby Rd, Nottingham NG7 2UH, UK. E-mail: Jayesh.Bhatt@nuh.nhs.uk

      There is widespread variation in the implementation and monitoring of and weaning off home oxygen therapy (HOT) in neonatal respiratory disease, and current guidance is based predominantly on expert consensus and clinical experience. The potential adverse consequences associated with hypoxia underline the importance of a structured approach to the management of HOT. Evidence suggests that a structured pathway for night-time and daytime weaning confers advantages for infants, families and healthcare services. Family-centred care and shared decision making are key to the discharge process and transition from the neonatal unit into the community. The technological advancements of oximeters require consideration for the analysis and interpretation of data. Further research is required to establish evidenced-based target mean SpO2 values and to determine the impact of different targets on long-term infant outcomes.

      Cite as: Everitt LH, Bhatt JM, Evans HJ. Structured approach to monitoring and weaning off home oxygen therapy in neonatal respiratory disease. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 133–146 [https://doi.org/10.1183/2312508X.10020620].

    1. Page 147
      Abstract
      Malcolm Brodlie, Level 3, Clinical Resource Building, Great North Children's Hospital, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK. E-mail: malcolm.brodlie@ncl.ac.uk

      Tracheal disorders presenting during the neonatal period range from minor problems requiring no specific intervention to life-threatening abnormalities. Tracheomalacia is the most common disorder, and may be primary, due to an intrinsic problem with the development of tracheal cartilaginous rings, or secondary to external compression, most commonly by a vascular ring caused by abnormal development of the great vessels. Tracheo-oesophageal fistulae are relatively common. Less frequent but potentially life-threatening disorders include tracheal stenosis or agenesis. The most appropriate investigations depend on the clinical situation but usually involve chest radiography, CT, bronchoscopy and tracheobronchography. A multidisciplinary approach in a specialist centre is crucial, involving respiratory physicians, neonatologists, radiologists, anaesthetists, cardiologists and surgeons as required. Management varies from a conservative approach to long-term pressure support, airway stenting or surgery.

      Cite as: Zainal Abidin N, Naples R, Powell S, et al. Tracheal disorders. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 147–163 [https://doi.org/10.1183/2312508X.10002021].

    2. Page 164
      Abstract
      Robert Thomas Peters, Manchester Paediatric and Neonatal Surgery, Royal Manchester Children's Hospital, Oxford Road, Manchester M13 9WL, UK. E-mail: r.peters@nhs.net

      Congenital lung malformation (CLM) is an umbrella term encompassing a number of lesions including CPAM, bronchopulmonary sequestration and congenital lobar emphysema. Most CLMs are detected antenatally, and rarely fetal intervention is required. Around 10% of neonates with CLM have persistent respiratory distress presenting at or soon after birth due to lesion size and require surgical resection. The majority of lesions, however, are asymptomatic at birth, and opinion on their management remains polarised between those advocating elective resection, in the first year of life, of most or all lesions and those arguing for expectant management. Arguments for both sides are based on the same themes: risk of developing symptoms (including sepsis and pneumothorax), potential for malignancy, opportunity for compensatory lung growth and how to follow up conservatively managed patients. Symptomatic neonates are most commonly operated on by open thoracotomy, whereas thoracoscopy should now be considered the gold standard for resections beyond the neonatal period and/or asymptomatic lesions. Thoracoscopy has clear benefits: reduced length of hospital stay, reduced complications and improved long-term lung function.

      Cite as: Peters RT, Singh M. Congenital parenchymal structural lung lesions: cysts, emphysema and sequestration. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 164–178 [https://doi.org/10.1183/2312508X.10014220].

    3. Page 179
      Abstract
      Paul D. Losty, Paediatric Surgery, University Of Liverpool, Eaton Road, Liverpool, UK. E-mail: paul.losty@liverpool.ac.uk

      CDH is a human birth defect associated with high mortality (>50%) and morbidity due to perturbed lung development. Advances in clinical care have steadily evolved from in utero diagnosis, better perinatal care pathways, elective delivery of newborns at specialist “high volume” centres, use of permissive hypercapnia (“gentle ventilation”) strategies and avoidance of barotrauma with stabilisation of labile cardiopulmonary physiology with delayed surgical repair. ECMO plays an increasingly vital supportive role for the critically ill newborn failing conventional ventilation. Fetal intervention using minimally invasive guided tracheal balloon occlusion in “high risk” CDH cases linked to fetal risk prognostic scoring (observed-to-expected lung area to head circumference ratio, and liver herniation) is currently the subject of a randomised clinical trial (TOTAL). This chapter provides a state-of-the-art update on current and future advances in CDH.

      Cite as: Boonthai A, Losty PD. Congenital diaphragmatic hernia. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 179–196 [https://doi.org/10.1183/2312508X.10014320].

    4. Page 197
      Abstract
      Andrew Bush, Dept of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E-mail: a.bush@imperial.ac.uk

      Pulmonary lymphangiectasia is a rare disorder that causes accumulation of lymph within the lungs and accounts for less than 1% of antenatal and perinatal deaths. Primary pulmonary lymphangiectasia results from abnormal lymphatic development and secondary pulmonary lymphangiectasia is due to obstruction of normal lymphatic flow. Lymphatic development is complex and controlled by multiple genes and can be impacted upon by numerous chromosomal disorders as well as environmental changes, such as infection. Presentations outside the neonatal period are also well recognised. Management requires extensive antenatal/post-natal investigations to find an underlying cause and supportive care is the mainstay of treatment; there is currently no known cure, although a variety of treatments are suggested anecdotally.

      Cite as: Bush A, Mayell S, Pabary R. Pulmonary lymphangiectasia. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 197–212 [https://doi.org/10.1183/2312508X.10014420].

    5. Page 213
      Abstract
      Nadia Nathan, Pediatric Pulmonology Dept, Armand Trousseau Hospital, 26 Avenue du Dr Arnold Netter, 75012 Paris, France. E-mail: nadia.nathan@aphp.fr

      Neonatal interstitial lung diseases (ILDs) are rare disorders with a high morbidity and mortality manifesting as severe respiratory insufficiency with frequent PH. The main causes are surfactant disorders, especially disorders of the proteins SP-B, SP-C, ABCA3 and NKX2-1, which can be diagnosed with molecular screening. Other aetiologies are developmental disorders that are more often diagnosed on lung biopsy or autopsy. The most frequent is alveolocapillary dysplasia with misalignment of pulmonary veins, often related to a FOXF1 mutation. The medical management of curable diseases is based mainly on corticosteroids. In some cases, lung transplantation may be discussed. The prognosis relies highly on the rapidity of the management, which should be provided by expert multidisciplinary teams including clinicians, paediatric radiologists, pathologists and geneticists. Genetic counselling should always be provided to the family, even if occurring after a fatal evolution of the disease. Often misdiagnosed and underestimated, neonatal ILD patients should be systematically reported in reference databases for children's ILD.

      Cite as: Soreze Y, Sileo C, Coulomb l'Hermine A, et al. Interstitial lung diseases. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 213–230 [https://doi.org/10.1183/2312508X.10014520].

    6. Page 231
      Abstract
      Christopher Grime, Alder Hey Children's NHS Foundation Trust, East Prescot Road, Liverpool, Merseyside L14 5AB, UK. E-mail: Christopher.Grime@alderhey.nhs.uk

      The term neuromuscular diseases (NMDs) covers a range of disorders resulting in the dysfunction of peripheral nerves, the neuromuscular junction or muscle tissue. A diagnosis of NMD during the newborn period carries a significant risk of respiratory failure due to neonatal reduced airway patency and skeletal muscle inefficiency. Several NMDs can present during the newborn period such as muscular dystrophies, including congenital myotonic dystrophy, congenital myopathies, myasthenia gravis, congenital myasthenic syndromes and spinal muscular atrophies. Apart from recent advances in disease-modifying treatments for chromosome 5q-related spinal muscular atrophy, for most of the conditions only supportive management is available. The focus of treatment is therefore on secretion management, chest-clearance physiotherapy, nutritional support and assessment of swallowing, with resulting feeding management strategies to ensure adequate nutrition but also airway protection to prevent aspiration. If respiratory failure is identified, there may be a need to introduce ventilatory support via noninvasive or invasive long-term ventilation. For all of the potential interventions proposed, the impact on quality of life of the infant should be considered.

      Cite as: Lund K, Grime C, Spinty S. Neuromuscular disease and respiratory failure. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 231–244 [https://doi.org/10.1183/2312508X.10014620].

    7. Page 245
      Abstract
      Elizabeth Whittaker, Section of Paediatric Infectious Diseases, Imperial College London, Norfolk Place, St Mary's Campus, London W2 1PG, UK. E-mail: e.whittaker@imperial.ac.uk

      Perinatal infection is an important cause of respiratory distress in the newborn period and may reflect exposures in utero, during labour and post-natally. It may progress to respiratory failure rapidly and result in significant morbidity and mortality if overlooked. Diagnosis includes a detailed history including maternal health and exposures, clinical examination, chest radiography, routine blood cultures and respiratory secretions for bacterial culture and viral PCR. The need for more specific investigations including maternal antenatal serology, placental culture and histology, infant serology and lumbar puncture may be guided by the history and examination. Empirical treatment with broad-spectrum antibiotics as per local guidelines should be initiated, pending further clinical information and response. The aetiology of infections is broad, including common bacterial infections, congenital infections, and more uncommon protozoan or viral infections and tuberculosis. Early recognition and treatment of neonatal infections prevents both short- and long-term complications.

      Cite as: Primhak S, Myttaraki E, Whittaker E. Congenital infections of the respiratory tract. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 245–258 [https://doi.org/10.1183/2312508X.10014720].

    8. Page 259
      Abstract
      Rebecca Thursfield, Dept of Respiratory Medicine, Alder Hey Children's NHS Foundation Trust, Eaton Road L12 2AP, Liverpool, UK. E-mail: rebecca.thursfield@alderhey.nhs.uk

      CF is a common inherited condition and may be diagnosed in the antenatal period following the persistence of abnormal echogenicity of the bowel or via prenatal carrier screening. More commonly, it is diagnosed post-natally via newborn bloodspot screening, following presentation with meconium ileus or later with clinical manifestations. Optimising nutrition in the early years has been shown to reduce later morbidity and mortality. For those infants presenting with meconium ileus, post-operative management can be challenging; therefore, care of these infants should be in a specialist CF centre familiar with such challenges. Although there have been significant advances in the use of CF transmembrane conductance regulator modulator therapies, these are currently not available within the neonatal period, but some are available from 6 months of age. There is evidence of early airway inflammation, and prompt initiation of airway clearance, prevention of infection as well as good nutrition are key in the early management of the newborn with CF. High-quality CF care in the neonatal period can only be provided by a multidisciplinary team.

      Cite as: Sadlers V, Woodland C, Walsh A, et al. Managing cystic fibrosis. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 259–272 [https://doi.org/10.1183/2312508X.10014820].

    9. Page 273
      Abstract
      Omendra Narayan, Royal Manchester Children's Hospital, Oxford Road, Manchester M13 9WL, UK. E-mail: Omendra.Narayan@mft.nhs.uk

      There is a paucity of data on neonatal sleep physiology, normative data and disorders. Newborns spend more than half of their sleep time in stage R (rapid eye movement) sleep. Sleep is an integral part of an infant's development, leading to adequate growth and memory consolidation. Circadian rhythm is established by ∼6 months of age. Hypopnoeas and apnoeas are common in infants, and the mean apnoea/hypopnoea index is higher in healthy newborns than in older children. Fragmented sleep in the neonatal period causes endothelial dysfunction and can lead to a poor neurodevelopmental outcome. Various sleep problems can occur throughout infancy, and preterm infants are more vulnerable than term infants.

      Cite as: Narayan O, Sinha A, Ibrahim R, et al. Sleep physiology and disorders. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 273–286 [https://doi.org/10.1183/2312508X.10014920].

    10. Page 287
      Abstract
      Michael T. Ashworth, Dept of Histopathology, Great Ormond St Hospital for Children, London, WC1N 3NN, UK. E-mail: Michael.Ashworth@gosh.nhs.uk

      Lung biopsy in neonates is rare, and its interpretation a highly specialised area. The lung biopsy demonstrates patterns of abnormality that are the end result of a complex interplay of multiple factors (genetic, epigenetic and environmental) and frequently represents the end of a sequence of progressive deviations from normal. Lung growth abnormality with deficient alveolarisation is the commonest pattern. While a small number of specific diagnoses, such as alveolar capillary dysplasia, can sometimes be rendered, a unifying diagnosis is seldom possible on histology alone, and the histological pattern evident on biopsy must be integrated into the clinical, radiological and genetic picture.

      Cite as: Ashworth MT, Hutchinson JC, Haini M. Histopathology of newborn lung disease. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 287–300 [https://doi.org/10.1183/2312508X.10015020].

    11. Page 301
      Abstract
      Musa Kaleem, Alder Hey Children's NHS Foundation Trust, East Prescot Road, Liverpool, L14 5AB, UK. E-mail: Musa.Kaleem@alderhey.nhs.uk

      Portable chest X-ray is the mainstay of neonatal chest imaging and is frequently used for the assessment of lines and tubes as well as for common neonatal lung pathologies. In this chapter, we discuss the different technical factors affecting radiographic quality, the normal variants mimicking pathology and the radiographic features of commonly encountered pulmonary conditions, such as surfactant deficiency lung disease, BPD, TTN, neonatal pneumonia and MAS. We also briefly describe other chest imaging techniques, including ultrasound and HRCT.

      Cite as: Kaleem M, Harave S. Chest radiology. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 301–319 [https://doi.org/10.1183/2312508X.10015120].

    12. Page 320
      Abstract
      Chris Dewhurst, Richard Cooke Neonatal Unit, Liverpool Women's Hospital NHS Foundation Trust, Crown Street, Liverpool L8 7SS, UK. E-mail: Christopher.dewhurst@lwh.nhs.uk

      MAS is a difficult condition to manage. For many years, interventions were practised with the aim of preventing newborns inhaling meconium at birth, but all were shown to be at best useless and potentially harmful. In this chapter, we describe the mechanisms of how meconium is inhaled and what effects it has on the lungs. Particular emphasis is placed on ventilation management, which is particularly difficult and requires the clinician to strike the balance between limiting interventions for those who require it, and timing these so that they commence early enough in the disease process to impact positively on the outcome. Finally, criteria for identifying when your patient is at risk of treatment failure and the need for escalation to ECMO are provided.

      Cite as: Thomas H, Dewhurst C. Meconium aspiration syndrome. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 320–335 [https://doi.org/10.1183/2312508X.10015220].

    1. Page 336
      Abstract
      Andrew Sharp, Women's and Children's Health, University of Liverpool, Liverpool Women's Hospital, Liverpool, UK. E-mail: a.sharp@liverpool.ac.uk

      The determinants of a child’s early years respiratory health are influenced by both the in utero and ex utero environment. In addition, obstetric conditions such as fetal growth restriction and preterm birth may contribute to the risk of respiratory health concerns in the neonate either due to a toxic in utero environment or the association of respiratory health with premature birth.

      Cite as: Busuulwa P, Sharp A. Socioeconomic determinants of early years respiratory health, and the impact on later life. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 336–342 [https://doi.org/10.1183/2312508X.10015320].

    2. Page 343
      Abstract
      Olukemi Tongo, Dept of Paediatrics, College of Medicine, University of Ibadan, Ibadan. E-mail: ktongo2@yahoo.com

      The majority of global neonatal mortalities occur in low- and middle-income countries (LMICs) with prematurity, infections and asphyxia being the commonest causes of death, and all three are major risk factors for respiratory distress. Respiratory distress is a common cause of neonatal admission with respiratory failure being a common final pathway to neonatal mortality. There is no evidence to suggest that the respiratory physiology in newborns in high-income countries differs from those in LMICs. The commonest cause of respiratory disease in term babies is neonatal infections while RDS is commonest among preterm infants. There is limited access to radiologic and other facilities for diagnosis and monitoring of newborn respiratory disease. Antimicrobial resistance contributes to management challenges. Surfactant replacement therapy shows promise in the treatment of RDS but is not readily available due to financial constraints. Easy to construct improvised bubble CPAP is effective and gaining wide acceptance for respiratory support in LMICs.

      Cite as: Tongo OO, Imam ZO. Low- and middle-income countries. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 343–349 [https://doi.org/10.1183/2312508X.10015420].

    3. Page 350
      Abstract
      Marlyse F. Haward, Weiler Division, Division of Neonatology, Children's Hospital at Montefiore, Medical Center, Albert Einstein College of Medicine, 1601 Tenbroeck Ave, 2nd Floor, Bronx, NY 10461, USA. E-mail: mhaward@aol.com

      Decisions arising during pregnancy and at delivery are complex, often creating tension between ethical principles, as well as conflicts between maternal and fetal/neonatal interests. These dilemmas can occur due to the uncertainty in neonatal outcomes for infants born at periviability, or arise from diagnoses of life-threatening chromosomal abnormalities or congenital anomalies that impair the function of vital organs. Under these circumstances, parents and physicians try to balance the values of sanctity of life with quality of life. Parents generally act as surrogate decision makers, while physicians retain obligations to safeguard the infant's best interests. Cultural and social norms can also play a role in influencing these decisions. This chapter will review the basic ethical principles as they apply to the unique dilemmas of pregnancy and childbirth, consider the antenatal consultation within cultural and societal norms, and lastly discuss country-specific delivery room management approaches.

      Cite as: Haward MF, Danziger PD, Wilson S, et al. The ethics of resuscitation. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 350–360 [https://doi.org/10.1183/2312508X.10015520].

    4. Page 361
      Abstract
      Eugenio Baraldi, Neonatal Intensive Care Unit, Dept of Women's and Children's Health, University of Padova, via Giustiniani, 3, 35128, Padova, Italy. E-mail: eugenio.baraldi@unipd.it

      RSV is a respiratory pathogen that is a frequent cause of hospital admissions during infancy every year in the epidemic season. This virus is particularly dangerous for some sensitive populations such as former preterm infants, especially if affected by BPD, and infants with CHD or immunodeficiency. There is no available therapy to date, so adequate prophylaxis in these populations is crucial to avoid major morbidities and mortality, especially in low-resources countries. Currently, the only available preventative strategy is monthly intramuscular administration of a monoclonal antibody (palivizumab), with positive results in selected populations. Current research aims to develop other preventative opportunities including other monoclonal antibodies with higher affinity and a longer half-life, but also vaccines, in particular, recombinant live attenuated vaccines for younger infants and inactivated (subunit and nanoparticle) vaccines for older infants and pregnant women to passively protect the newborn infant.

      Cite as: Bonadies L, Priante E, Baraldi E. Prophylaxis against respiratory syncytial virus in high-risk infants. In: Sinha IP, Bhatt JM, Cleator A, et al., eds. Respiratory Diseases of the Newborn Infant (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 361–371 [https://doi.org/10.1183/2312508X.10015620].